The present invention is directed to a pharmaceutical preparation for the treatment of hemorrhagic shock and the sequels thereof.
Shock is an acute complication of many different pathological conditions characterized by the inability of the cardiovascular system to maintain an adequate perfusion pressure. More specifically, in hemorrhagic shock, blood loss exceeds the body's ability to compensate and provide adequate tissue perfusion and oxygenation. This frequently is due to trauma, but it may be caused by spontaneous hemorrhage (eg, GI bleeding, childbirth), surgery, and other causes.
Most frequently, clinical hemorrhagic shock is caused by an acute bleeding episode with a discrete precipitating event. Less commonly, hemorrhagic shock may be seen in chronic conditions with subacute blood loss. This condition is the leading cause of death in the age group of 1-44.
Physiologic compensation mechanisms for hemorrhage include initial peripheral and mesenteric vasoconstriction to shunt blood to the central circulation. This is then augmented by a progressive tachycardia. Invasive monitoring may reveal an increased cardiac index, increased oxygen delivery (ie, DO2), and increased oxygen consumption (ie, VO2) by tissues. Lactate levels, the acid-base status, and other markers also may provide useful indicators of physiologic status. Age, medications, and comorbid factors all may affect a patient's response to hemorrhagic shock.
Failure of compensatory mechanisms in hemorrhagic shock can lead to death. Without intervention, a classic trimodal distribution of deaths is seen in severe hemorrhagic shock. An initial peak of mortality occurs within minutes of hemorrhage due to immediate exsanguination. Another peak occurs after 1 to several hours due to progressive decompensation. A third peak occurs days to weeks later due to sepsis and organ failure, which is a frequent consequence of reperfusion damage to the organs.
Treatment of shock caused by major blood loss is a great challenge, because secondary effects involving an inflammatory reaction and alterations in the coagulation system may have become independent and lead to the death of the patient irrespective of the question, whether adequate fluid and blood replacement has been possible. Specific treatment of major blood loss due to accidents or other wounds and of hemorrhagic shock consists of fluid resuscitation with crystalloids or colloids in order to reestablish organ perfusion. In addition, current procedures aim to relieve symptoms, which includes mechanical ventilation, fluid replacement, the use of cardio active drugs, strict control of oxygen saturation, hemoglobin, glucose and renal function. The control of the inflammation reaction only, e.g. with high dosage steroids or the inhibition of coagulation with anti thrombin, does not produce improvement of survival.
Shock as a sequel of blood loss and hemorrhagic shock is associated with overt or non-overt changes in plasma fibrinogen accompanied by fibrin formation and by an increase in fibrin fragments. This activation of clotting as well as fibrinolytic pathways may result in overt or non-overt disseminated intravascular coagulation (DIC) resulting in vessel occlusion and end-organ damage, and in consumption of coagulation factors resulting in bleeding. Importantly, fibrinogen, fibrin and fibrin fragments play not only a role in blood coagulation, but have several binding sites for cellular and matrix proteins, which allow them to interact with white blood cells, platelets, endothelial cells and matrix structures. This leads to cell activation, cell migration, cytokine release and ultimately to an inflammatory reaction. The role of fibrinogen or fibrin in inflammation is amply documented (reviewed by Altieri Thromb Haemost 82:781-786; Herrick et al. Int J Biochem Cell Biol 31:741-46). The D-region of the molecule contains many binding sites for matrix molecules, endothelial cells, platelets and inflammatory cells. The E-region of fibrin binds to CD11c (Loike et al. Proc Natl Acad Sci USA 88:1044-48).
We have recently described a novel role for the Bbeta15-42 sequence of fibrin in inflammation (WO 02/48180). This sequence is also located within the E-region of fibrin and is only active when fibrinopeptide is cleaved. Fibrin fragments containing this sequence at their free N-terminus of the beta chain bind to endothelium and cause inflammation, and a peptide matching the aminoacids 15-42 of the Bbeta chain of fibrin blocks binding of fibrin fragments to endothelial surfaces and blocks inflammation in vitro (WO 02/48180). In vivo, this petide prevents myocardial inflammation and reduces myocardial infarct sizes in situations of ischemia/reperfusion (WO 02/48180).
Fibrin fragments occur in any situation of impaired fibrin formation and impaired fibrinolysis. Specifically in situations of shock this altered fibrin formation and fibrinolysis is a major problem. For many diseases a direct correlation between the outcome and the impairment of fibrin formation/fibrinolysis has been documented. E.g. Dengue (van Gorp et al. J Med Virol 2002, 67:549-54, Mairuhu et al. Lancet Inf Dis 2003; 3:33-41). Adult respiratory distress syndrome (ARDS) is a form of acute lung injury that is characterized by florid extravascular fibrin deposition (Idell Am J Respir Med. 2002; 1:383-91). Thrombosis in the pulmonary vasculature and disseminated intravascular coagulation have also been observed in association with ARDS.